This invention relates to a process for making the imino sugar D-1-deoxygalactonojirimycin (DGJ) the generic name of which is migalastat.
Migalastat can be used in the treatment of Fabry disease (Fan et al., Nat Med 1999 5:1, 112-5). There are several chemical routes to migalastat disclosed in the literature. Santoyo-Gonzalez et al., Synlett 1999 593-595 describes the synthesis of migalastat from D-galactose, by a chemical route comprising eight steps including undesirable azide chemistry. A twelve-step chemical route to migalastat starting from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose is described by Legler & Pohl, Carbohydr. Res., 155 (1986) 119-129. The final step of this process involves converting galactostatin bisulfite adduct to migalastat. Migalastat has also been synthesised from galactopyranose (Bernotas et al., Carbohydr. Res. 167 (1987) 305-11); L-tartaric acid (Aoyagi et al., J. Org. Chem. 56 (1991) 815); quebrachoitol (Chida et al., J. Chem. Soc., Chem Commun. 1994, 1247); galactofuranose (Paulsen et al., Chem. Ber. 1980, 113, 2601); benzene (Johnson et al., Tetrahedron Lett. 1995, 36, 653); arabino-hexos-5-ulose (Barili et al., Tetrahedron 1997, 3407); 5-azido-1,4-lactones (Shilvock et al., Synlett, 1998, 554); deoxynojirimycin (Takahashi et al., J. Carbohydr. Chem. 17 (1998) 117); acetylglucosamine (Heightman et al., Helv. Chim. Acta 1995, 78, 514); myo-inositol (Chida N, et al., Carbohydr. Res. 1992 Dec. 31; 237: 185-94); dioxanylpiperidene (Takahata et al., Org. Lett. 2003; 5(14); 2527-2529); and (E)-2,4-pentadienol (Martin et al., Org Lett. 2000 January; 2(1):93-5, Hughes et al., Nat Prod Rep. 1994 April; 11(2):135-62). WO2008/045015 (Amicus Therapeutics, Inc) describes another chemical process for the preparation of migalastat.
Problems with the existing, chemical processes to migalastat are that they are costly, require at least an eight stage process, and include potentially hazardous azidation chemistry. It would be beneficial if migalastat could be produced by a more cost effective and sustainable process. Fermentation processes are well established in industry as a means to produce biological molecules such as antibiotics, amino acids and vitamins at large scale and relatively low cost (Atkinson, & Mavittma, Biochemical Engineering and Biotechnology Handbook, 2nd Edition, New York, Stockton Press, 1991). Although galactostatin has previously been isolated as its bisulfite adduct from the culture broth of Streptomyces lydicus PA-5726 (Miyake and Ebata, Agric. Biol. Chem., 52(7), 1649-1654 (1988)), hitherto no known microorganisms have been identified as producing migalastat.